Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients ...with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A.
We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose one participant, intermediate dose one participant, and high dose seven participants) and were followed through 52 weeks.
Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected.
The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with stabilization of hemostasis and a profound reduction in factor VIII use in all seven participants. In this small study, no safety events were noted, but no safety conclusions can be drawn. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795 ; EudraCT number, 2014-003880-38 .).
The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of patients infected worldwide and indirectly affecting even more individuals through disruption of daily living. Long-term ...adverse outcomes have been reported with similar diseases from other coronaviruses, namely Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). Emerging evidence suggests that COVID-19 adversely affects different systems in the human body. This review summarizes the current evidence on the short-term adverse health outcomes and assesses the risk of potential long-term adverse outcomes of COVID-19. Major adverse outcomes were found to affect different body systems: immune system (including but not limited to Guillain-Barré syndrome and paediatric inflammatory multisystem syndrome), respiratory system (lung fibrosis and pulmonary thromboembolism), cardiovascular system (cardiomyopathy and coagulopathy), neurological system (sensory dysfunction and stroke), as well as cutaneous and gastrointestinal manifestations, impaired hepatic and renal function. Mental health in patients with COVID-19 was also found to be adversely affected. The burden of caring for COVID-19 survivors is likely to be huge. Therefore, it is important for policy makers to develop comprehensive strategies in providing resources and capacity in the healthcare system. Future epidemiological studies are needed to further investigate the long-term impact on COVID-19 survivors.
Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single ...administration of AAV5-hFVIII-SQ.
We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years.
Three years after infusion, two participants (one who had received 6×10
vector genomes vg per kilogram of body weight and one who had received 2×10
vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×10
vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×10
vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed.
Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10
vg per kilogram or 6×10
vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.).
Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic ...profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations that maximize these plasma cell metabolic properties might thus provide enduring antibody-mediated immunity.
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•LLPCs import more glucose than do short-lived plasma cells (SLPCs)•LLPCs primarily use glucose to glycosylate antibodies•Under metabolic stress, LLPCs but not SLPCs divert glucose to form pyruvate•Genetic ablation of mitochondrial pyruvate import shortens the lifespan of LLPCs
Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs), but specific pathways that allow LLPC persistence are unknown. Bhattacharya and colleagues show that LLPCs import and use glucose for antibody glycosylation, but in times of metabolic stress, they divert glucose to generate pyruvate for survival.
Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective ...promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study.
We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×10
vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results.
Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval CI, 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants.
In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).
Plasma cell survival and the consequent duration of immunity vary widely with infection or vaccination. Using fluorescent glucose analog uptake, we defined multiple developmentally independent mouse ...plasma cell populations with varying lifespans. Long-lived plasma cells imported more fluorescent glucose analog, expressed higher surface levels of the amino acid transporter CD98, and had more autophagosome mass than did short-lived cells. Low amino acid concentrations triggered reductions in both antibody secretion and mitochondrial respiration, especially by short-lived plasma cells. To explain these observations, we found that glutamine was used for both mitochondrial respiration and anaplerotic reactions, yielding glutamate and aspartate for antibody synthesis. Endoplasmic reticulum (ER) stress responses, which link metabolism to transcriptional outcomes, were similar between long- and short-lived subsets. Accordingly, population and single-cell transcriptional comparisons across mouse and human plasma cell subsets revealed few consistent and conserved differences. Thus, plasma cell antibody secretion and lifespan are primarily defined by non-transcriptional metabolic traits.
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•Plasma cells with varying lifespans are distinguished by fluorescent glucose uptake•Lifespan is associated with antibody secretion, autophagy, and nutrient uptake•Endoplasmic reticulum stress responses are similar across all plasma cell subsets•Conserved transcriptional changes are not observed in long-lived subsets
Plasma cell survival and the consequent duration of immunity vary widely with infection or vaccination. Lam et al. demonstrate that short- and long-lived plasma cells are distinguished by metabolic properties such as nutrient uptake. In contrast, very few conserved transcriptional changes are observed between plasma cells of varying longevity.
Burden of mild haemophilia A: Systematic literature review Peyvandi, Flora; Tavakkoli, Fatemeh; Frame, Diana ...
Haemophilia : the official journal of the World Federation of Hemophilia,
September 2019, Letnik:
25, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Introduction
Although the clinical manifestations of severe haemophilia A (HA) are well studied, the challenges, if any, of living with mild HA are not clearly delineated to date.
Aim
To assess ...available evidence of clinical risks and societal/economic impacts of disease in adult patients with mild HA using a systematic literature review.
Methods
Prespecified study selection criteria were applied in a comprehensive literature search. Included studies varied in design and reported outcomes of interest for adults (≥13 years of age) with mild HA.
Results
Seventeen studies with a total of 3213 patients met eligibility criteria (published or presented in English, 1966‐2017). Most studies were observational, and the outcomes reported were too sparse and dissimilar to support a formal meta‐analysis. Mean annual bleeding rates ranged from 0.44 to 4.5 episodes per patient per year. Quality of life (QoL; SF‐36 General Health) was impacted compared to healthy controls. Health care costs and productivity were seldom assessed and no robust comparisons to healthy controls were available.
Conclusion
Quantifying outcomes for adult patients with mild HA remains challenging, with estimates of key QoL and cost data often based on small data sets and without comparison to population norms. Therefore, the clinical impact of mild haemophilia may be under‐represented and unmet needs may remain unaddressed. As paradigm‐changing therapies for HA emerge, stronger knowledge of mild HA can guide the development of care options that minimize burden and enhance the QoL for this segment of the haemophilia community, and for the haemophilia community in totality.
Purpose This study was to evaluate the efficacy of a complementary Chinese treatment modality Guolin-Qigong (GLQG) for patients with breast cancer on the body-mind health. Methods A randomized ...controlled clinical trial was conducted among 158 women with breast cancer. Subjects were randomized to receive GLQG (test group) versus a physical stretching program (control group) following conventional treatment for breast cancer. GLQG and stretching interventions were performed twice a week over 24 weeks. The primary outcome was the change in quality of life (QoL). Secondary outcome measures included anxiety, depression, and clinical indicators. All participants were assessed at four time-points, at the beginning of the study (T1), after 12 weeks of the intervention (T2), immediately after 24-week intervention (T3), and at 48-week follow-up visit (T4). Results Improvements in QoL were evident in both groups but the test group fared better than the control group at the 12th week (P < 0.01) and particularly in emotional wellbeing (P < 0.01) and breast cancer-specific well-being (P < 0.001). The test group showed an improvement in anxiety levels (P < 0.01), whereas the control group showed improvements in depression (P < 0.05) but there was no significant difference between groups (P > 0.05). Both groups showed improvements in immunological function and the test group fared better than the control in TNF-α levels (P < 0.05). The results in subjects who practiced more than 4 times and 6 h per week were similar to that of all subjects; however, the improvement in anxiety in the GLQG group was more obvious. There are positive correlations between QoL and anxiety and depression. Conclusions Both GLQG and physical stretching are beneficial during recovery following breast cancer. GLQC was more effective in terms of Qol improvements than physical stretching. Both programs brought improvements in anxiety or depression but had were comparable. GLQC group had a greater effect on immunological function than physical exercise.
Sodium fluoroacetate (1080) is a toxic metabolic poison with no known antidote. Its use is strictly regulated within the United States, but it is commonly used as a pesticide in Australia, Israel, ...Japan, Mexico, New Zealand, and South Korea. 1080 has been identified as a possible terrorist weapon, and exposure is extremely difficult to diagnose given its overlapping symptoms with other common diseases. An abandoned U.S. patent indicated that methylene blue (MB) could be used as a potential countermeasure to 1080 poisoning when combined with monosodium glutamate (MSG). In this study, MB was used as a stand‐alone treatment to determine if it is capable of rescuing cellular metabolism or decreasing 1080 lethality.
Male Sprague‐Dawley rats were exposed to increasing concentrations of 1080 (0.5, 1.1, 2.1, 4.2, and 8.4 mg/kg) based on a LD50 logarithmic scale. A low dose of MB (11 mg/kg) was administered via intraperitoneal injection (i.p.) at 0.5 hr and 2 hr post‐exposure. Euthanasia occurred 24 hours post‐exposure and blood was collected from the descending aorta. Serum was separated after collection and stored at ‐80 °C. Bronchoalveolar lavage fluid (BALF) was also collected from the right lung using phosphate buffered saline (PBS) and then stored at ‐80 °C. Gas chromatography‐mass spectrometry (GCMS) was performed on serum samples to identify potential metabolic compounds of interest. From the GCMS data, L‐carnitine and methylmalonic acid (MMA) were proposed as potential markers of 1080 exposure. To quantitate circulating levels, an L‐carnitine colorimetric/fluorometric assay and a methylmalonic acid enzyme‐linked immunosorbent assay (ELISA) were performed. Based on previous data indicating cardiopulmonary effects of 1080, a high sensitivity rat cardiac troponin‐I ELISA was used to determine cardiac damage, and BALF was tested for the presence of protein and hemoglobin.
The coenzyme‐A linked form of MMA is converted into succinyl‐CoA for use in the TCA cycle. MMA levels were relatively low and unchanged across all groups, except for rats receiving a 1.1 mg/kg dose of 1080. L‐carnitine is a compound involved in metabolism via the carnitine shuttle system, and is activated when ATP concentration decreases, allowing transport of fatty acid chains into the mitochondria to help replenish the ATP supply. Carnitine levels varied across the exposure concentrations in the groups treated with MB, but at the 2.1 mg/kg exposure dose, treatment with MB appeared to decrease the amount of circulation carnitine. Hemorrhagic pulmonary edema is a symptom of 1080 poisoning, and MB was able to significantly reduce the presence of hemoglobin in BALF for 0.5, 1.1, and 2.1 mg/kg groups. Treatment with MB was able to shift the LD50 curve of 1080 to 3.29 mg/kg from 2.18 mg/kg, giving a protective ratio of 1.53. MB was also able to increase the probability of survival of animals at the 8.4 mg/kg exposure dose. Overall, while MB has shown some promise as treatment for 1080, further testing is needed to determine how viable it is and identify any likely biomarkers for screening to lead to an accurate diagnose.
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